Respiratory pattern generation and motor output integration are strongly influenced by behavioral state. In particular, rapid eye movement (REM) sleep is associated with increased variability of respiratory timing and effort. In extreme cases, the respiratory dysrhythmia permitted or provoked during REM sleep appears to be a pathogenic factor for sleep-related breathing disorders such as sleep apnea syndrome. The neuronal networks and synaptic mechanisms that render respiratory outputs more labile during REM sleep remain poorly defined, but during the first funding cycle of this research program we developed key evidence supporting a discrete respiratory modulating region (RMR) within the pedunculopontinetegmental (PPT) nucleus of the pons. The PPT also is an important region for REM sleep homeostasis. We showed that PPT stimulation produced respiratory dysrhythmia in sleeping and anesthetized animals and this application presents preliminary evidence that PPT lesions reduce apnea expression during REM sleep. During years 6 to 10 we will pursue 3 specific aims to determine the anatomical localization, synaptic regulation, and physiological relevance of neurons in the RMR for state-dependent control of respiratory pattern variability. Aim 1 will employ nanoliter injections of glutamate and polygraphic monitoring to test the hypothesis that the RMR is anatomically distinct from regions within the PPT responsible for regulation of REM sleep and associated phenomena, including: EEG activation, hippocampal theta rhythm, and ponto-geniculo-occipital wave generation. Aim 2 will test the hypothesis that making excitotoxic lesions to the functionally identified RMR will decrease respiratory variability during sleep, and in particular during REM sleep. Defining the characteristic extent of the RMR in Aim 1 will help us to tune the size of these lesions, and we will correlate the extent of cell loss with the respiratory impact. Aim 3 will use injections of agonists and antagonists of, and immunohistochemistry for specific glutamate receptor subtypes to define the synaptic regulation of RMR neurons by glutamate. Extending the progress of the first funding cycle, these aims will provide important insights regarding the state-dependent mechanisms by which the PPT modulates respiratory pattern.